The following discussion is intended to facilitate the understanding of the invention, but is not intended nor admitted to be prior art to the invention.
Obesity is a public health problem that is serious, widespread, and increasing. In the United States, 20 percent of the population is obese; in Europe, a slightly lower percentage is obese (Friedman (2000) Nature 404:632-634). Obesity is associated with increased risk of hypertension, cardiovascular disease, diabetes, and cancer as well as respiratory complications and osteoarthritis (Kopelman (2000) Nature 404:635-643). Even modest weight loss ameliorates these associated conditions.
While still acknowledging that lifestyle factors including environment, diet, age and exercise play a role in obesity, twin studies, analyses of familial aggregation, and adoption studies all indicate that obesity is largely the result of genetic factors (Barsh et al (2000) Nature 404:644-651). In agreement with these studies, is the fact that an increasing number of obesity-related genes are being identified. Some of the more extensively studied genes include those encoding leptin (ob) and its receptor (db), pro-opiomelanocortin (Pomc), melanocortin-4-receptor (Mc4r), agouti protein (Ay), carboxypeptidase E (fat), 5-hydroxytryptamine receptor 2C (Htr2c), nescient basic helix-loop-helix 2 (Nhlh2), prohormone convertase 1 IPCSK1), and tubby protein (tubby) (rev'd in Barsh et al (2000) Nature 404:644-651).
The gene encoding leptin, one of the most widely studied obesity genes, is involved in the mechanisms of satiety (rev'd in Schwartz et al (2000) Nature 404:661-671). Leptin is a plasma protein of 16 kDa produced by adipocytes (Zhang et al ((1994) Nature 372:425-432). Mice with an autosomal recessive mutation in this gene (ob/ob mice) are obese and hyperphagic. Similarly, mice with an autosomal recessive mutation of the leptin receptor (db/db mice, for example) are also obese (Campfield et al (1995) Science 269:546-549). Administration of leptin to ob/ob, but not db/db, mice corrects their relative hyperphagia and allows normalization of their weight (Weigle (1995) J. Clin. Invest. 96:2065-2070).
Leptin circulates in the body at levels proportional to body fat content (Considine et al (1996) New Eng J Med 334:292-295) and enters the central nervous system (CNS) at levels proportional to the plasma level (Schwartz et al (1996) Nature Med 2:589-593). Leptin receptors are expressed by brain neurons involved in energy intake (Baskin et al (1999) Diabetes 48:828-833; Cheung et al (1997) Endocrinology 138:4489-4492) and administration of leptin into the brain reduces food intake (Weigle (1995) J. Clin. Invest. 96:2065-2070; Campfield et al (1995) Science 269:546-549), whereas its deficiency increases food intake (Zhang et al (1994) Nature 372:425-432).
Despite this clear evidence of leptin's role as an adiposity signal, with only a few exceptions the genes encoding leptin or its ob receptor have proved to be normal in obese human subjects (Kopelman et al (2000) Nature 404:635-643). Furthermore, and paradoxically, the plasma concentrations of leptin, are abnormally high in most obese human subjects (Considine et al (1996) New Eng J Med 334:292-295).